KR20150046110A - Methods of administering pirfenidone therapy - Google Patents

Abstract

This disclosure relates to an improved method of administering pyripenidone when ciprofloxacin is co-administered.

Description

[0001] METHODS OF ADMINISTERING PIRFENIDONE THERAPY [0002]

Cross-reference to related application

This application claims priority to provisional U.S. Patent Application Serial No. 61 / 696,044, filed August 31, 2012; Provisional U.S. Patent Application Serial No. 61 / 709,125, filed October 2, 2012; Provisional U.S. Patent Application Serial No. 61 / 749,026, filed January 4, 2013; Provisional U.S. Patent Application Serial No. 61 / 775,240, filed March 8, 2013; And Provisional U.S. Patent Application Serial No. 61 / 842,706, filed July 3, 2013, under 35 USC § 119 (e), the entire contents of each of which are incorporated herein by reference.

This disclosure relates to an improved method of administering a therapeutic agent for pypnidone when ciprofloxacin is co-administered, and to novel therapeutic doses of pypnidolone.

Pypenidone is a small molecule with a molecular weight of 185.23 daltons, the chemical name being 5-methyl-1-phenyl-2- (1H) -pyridone. Pirfenidone has antifibrotic properties and has been studied for therapeutic benefit in patients suffering from various fibrotic diseases. It is approved for the treatment of idiopathic pulmonary fibrosis (IPF) in Japan under the trade name Pirespa® and in many European countries under the trade name Esbriet®.

It has been confirmed that pypenidone is metabolized by various isotypes of cytochrome P450 (CYP) protein [Refer to the report on the evaluation of the Ministry of Health, Food and Drug Administration and the results of deliberations by the licensing department on September 16, 2008]. Specifically, several cytochrome P450 (CYP) isotypes (CYP1A2, 2C9, 2C19, 2D6, and 2E1) have been reported to be involved in the initial stage of pyperidone oxidative metabolism. More recently, it has been reported that pypnidol metabolism has been confirmed in in vitro experiments predominantly by CYP1A2 [US Pat. No. 7,816,383, which is incorporated herein by reference in its entirety).

Ciprofloxacin is a broad-spectrum antibacterial agent. Ciprofloxacin hydrochloride, USP and fluoroquinolone are used as monohydrochloride derivatives of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid Chloride monohydrate salt. It has a molecular weight of 385.8, and the empirical formula is C ₁₇ H ₁₈ FN ₃ O ₃ and HCl and H ₂ O, the chemical structure is as follows:

Ciprofloxacin was previously classified by the FDA as a moderate inhibitor of CYP1A2 [September 2006, draft FDA guidance on relevance to industrial drug interaction studies - study design, data analysis, and dosing and labeling] ; This description was recently revised in the February 2012 Guideline draft [February 2012, draft FDA guidance on relevance to industry drug interaction studies - study design, data analysis, and recommendations for dosing and labeling].

The present disclosure relates generally to improved use of pyrennydon and methods of administering pyrennydon to a patient in need of pyrennidone treatment and corresponding methods of manufacturing or packaging pyrennydon drugs, . This disclosure also relates to pyperpinidone for corresponding use in treating patients in need of pyplanidone therapy, including the use of novel therapeutic doses.

This disclosure discloses that pyripenidone at a dose of 801 mg (for example, three times daily for a total daily dose of 2403 mg / day) and a dose of 750 mg (e.g., 1500 mg / day Based on the finding that simultaneous administration of ciprofloxacin to a total daily dose of 2 times per day produces a moderate but significant rise in pypenidone exposure up to an average of about 1.8-fold. Thus, for example, a patient receiving a daily dose of 2403 mg may be exposed to a level of pyrethroidine equivalent to a dose of about 4325 mg of pyrethroid.

Thus, in one aspect, the present disclosure provides a method of treating a patient suffering from a condition selected from the group consisting of: (1) the possibility of reducing the clearance of pypnidone and / or (2) the possibility of increasing exposure to pyperidone It should be noted that ciprofloxacin should not be used (eg, avoided) in doses higher than 750 mg with pypenidone. Such improved uses and methods include not only avoiding the simultaneous use of ciprofloxacin (or avoiding concurrent use of pypnidone during ciprofloxacin administration) at doses of 750 mg or more, or 700 mg or more during the administration of pypenidone, And stopping the pyphenidone during the time interval in which ciprofloxacin is used.

In a first embodiment, for example, the disclosure provides a method of treating a patient suffering from cirrhosis, comprising administering to a patient a therapeutically effective amount of pypenidone, and administering 750 mg or more, e.g., 750 mg of ciprofloxacin - < / RTI > administration of pyripenidone therapy to a patient in need thereof. In any of the aspects or embodiments of the disclosure, the method comprises administering to a patient a therapeutically effective amount of pyphenidone, and administering a co-administration of ciprofloxacin at a dose of about 650 mg to about 850 mg, or about 700 mg to about 800 mg, There is provided a method of administering a pypnnidone treatment to a patient in need of pypnnidone treatment, which comprises administering the pypnidone treatment to a subject in need thereof. In some embodiments, the dose of ciprofloxacin is administered to the patient twice daily (i. E., BID) for a total daily dose of 1500 mg per day.

In an embodiment of such a method, for example, quadrupide is administered at an oral dose of about 800 mg or about 801 mg, and oral dosage of 750 mg or more, or about 650 mg to about 850 mg, or about 700 mg to about Simultaneous administration of ciprofloxacin at a dose of 800 mg is avoided. In one embodiment, the disclosure provides a method wherein ciprofloxacin doses of less than 750 mg, or less than 700 mg, or less than 650 mg (e. G., About 500 mg) are administered to a patient. In another embodiment, an alternative antibiotic therapeutic agent that is not ciprofloxacin is administered to the patient. It is contemplated to avoid simultaneous use of pyperpidon and ciprofloxacin at equivalent doses by other routes.

In a first embodiment, the disclosure also relates to a pharmaceutical composition comprising a compound of formula I in a dosage of 750 mg or more, or a dosage of about 650 mg to about 850 mg, or about 700 mg to about 800 mg, for example, The present invention provides a method of administering pypenidone therapy to a patient in need of pypenidone therapy, comprising stopping pyphenidone during the time interval in which ciprofloxacin is used. For example, in such an embodiment, the pyperidone is stopped before the time interval in which ciprofloxacin is administered to the patient, and the pyperidone is restarted after the time interval. Suspension and / or resumption may occur within one day or one week, for example, the time interval in which ciprofloxacin is used at the same time. The time interval in which ciprofloxacin is used may be any suitable time interval, such as one week, two weeks, three weeks, or one month. In a related embodiment, the pypnidone is stopped during the simultaneous administration of ciprofloxacin to an equivalent volume by another route.

The present disclosure is also based in part on finding a novel therapeutic dose of pypenidone for the treatment of patients who are co-administered with ciprofloxacin.

In a second embodiment, the disclosure provides a pharmaceutical composition comprising ciprofloxacin at a dosage of 750 mg, or at a dosage of about 650 mg to about 850 mg, or about 700 mg to about 800 mg, for example at a dosage of 750 mg twice daily During co-administration, the patient is administered pyropenidone therapy to a patient in need of treatment with pypnnidone, including reducing the dose of pypnenidone administered to the patient, for example, from about 1/2 to about 1/3 And provides an improved method. For example, if the patient is administered approximately 2400 or 2403 mg / day fiphenidone (provided, for example, 801 mg three times a day) prior to the administration of ciprofloxacin, the method comprises (a) administering about 1600 or 1602 mg / day, and (b) co-administration of ciprofloxacin at 750 mg twice daily (i. e., 1500 mg / day). do. In certain embodiments, when the pyrexenid unit dosage form is 267 mg capsules and pyperidymon is administered in 3 capsules three times daily, each dose of pyperidone in step (a) is administered three times daily It is reduced to two capsules. As another example, when a patient is administered 1800 mg / day furfenidone (e.g., 600 mg three times a day), the method comprises administering 1200 mg / day (400 mg / day) (B) co-administration of ciprofloxacin at 750 mg twice daily.

The present disclosure also encompasses administration of ciprofloxacin at a dose of about 650 mg to about 850 mg, or about 700 mg to about 800 mg, for example, at a dose of 750 mg twice a day, / 2 to about 1/3 of the total daily dose. The present invention further contemplates the use of pyrennydon in one or more unit dosage forms. In certain embodiments, where the pyrexenid unit dosage form is 267 mg capsules, the present invention encompasses the use of 1602 mg of the total of 1602 mg of the present invention in two unit doses three times per day for a patient receiving 750 mg ciprofloxacin concurrently twice daily, To provide the use of pyrenendin in a daily dose. Accordingly, the present invention also contemplates pharmaceutical compositions comprising a pharmaceutically acceptable excipient, and at least one unit dosage form for such use, which comprises 1602 mg / day pyphenidone.

Pharmaceutically acceptable excipients refer to materials used to formulate pharmaceutical products, such as disintegrants, binders, fillers, and lubricants, which are not active pharmaceutical ingredients, which will be well known to those skilled in the art. In an embodiment of the pharmaceutical composition of the present invention, the dosage unit may be a capsule, for example, a capsule containing 267 mg of pyrenpyridone and a pharmaceutically acceptable excipient.

In a related embodiment, the present disclosure relates to the reduced dose of pypnnidone during the simultaneous administration of ciprofloxacin when the drug (s) are provided in equivalent doses by different routes. Three times daily (every 8 hours) Intravenous (iv) administration of ciprofloxacin 400 mg i.v. is considered equivalent to 750 mg administered orally twice daily.

As used herein, "co-use" is understood to be used interchangeably with co-administration or co-administration. Thus, the terms refer to administration of the two agents at the same time, at different times, and by the same route or by different routes, as long as the two agents are administered in such a way that the agents of both can affect the body at the same time . For example, concurrent use can refer to co-administered drugs whether they are prescribed by the same or different genera, or for the same or different indications. For the administration route, the preferred route of administration according to the present disclosure is oral administration. In addition, the drug may be administered parenterally, for example, by any standard route of administration, including by intravenous, intraperitoneal, intrapulmonary, subcutaneous or intramuscular, epidural, intravenous, rectal, oral, And transmitted to the patient.

In any of the embodiments or embodiments, the patient may have idiopathic pulmonary fibrosis (IPF), bronchiolitis obliterans (BO), renal fibrosis or scleroderma, and the medicament, use or administration is for the treatment of such fibrosing diseases. In any of the embodiments or embodiments, the therapeutically effective amount of pypnnidone administered prior to requiring ciprofloxacin therapy can be about 2400 mg per day, for example, a daily dose of 2403 mg per day. In any of the aspects of the present disclosure, the daily dose may be administered in a divided dose of three times a day, or twice daily, or alternatively administered in a single dose once daily. In any of the aspects of the present disclosure, pyrennydon may be administered with the food. For example, a daily oral dose of 2,400 mg or 2403 mg of furfenidone per day may be administered as follows: 800 mg or 801 mg administered three times per day with food. Similarly, a daily oral dose of 1600 mg or 1602 mg furfenidone per day may be administered at 534 mg administered three times per day with food. In certain embodiments, pypnidone may be administered in an oral unit dosage form, such as a capsule or tablet. In certain embodiments, the amount of pyrennydone in the unit dosage form is 200 mg or 267 mg.

In any of the aspects or embodiments of the disclosure, the patient is understood to be in need of treatment with ciprofloxacin.

In some embodiments, ciprofloxacin at a dosage of 750 mg, for example, 750 mg twice a day, is used with caution when administering pypnnidone. In a further embodiment, ciprofloxacin at about 650 mg to about 850 mg, or at about 700 mg to about 800 mg, e.g., twice daily, is used with caution when administering pyperidone.

A further aspect of the disclosure provides a method of treating ciprofloxacin in a patient in need of such treatment wherein the treatment comprises the administration of ciprofloxacin at a dose of 750 mg twice daily, (E.g., up to about one-third) the dose of ciprofloxacin, or the use of ciprofloxacin at a dose of 750 mg. ≪ / RTI > in the manufacture of a medicament for use as a medicament. It is also understood that this applies to ciprofloxacin at doses of from about 650 mg to about 850 mg or from about 700 mg to about 800 mg.

For ease of administration and improved safety, the present invention also encompasses a method of treating a patient in whom ciprofloxacin and pyperidone are co-administered (e. G., At any of the doses given twice a day, 250 mg, 500 mg, or 750 mg) With a reduced dose of about 1602 mg / day, or about 1600 mg / day, or about 1/3 (from a baseline dose, for example, 1800 mg / day or 2403 mg / day) .

For ease of administration and improved safety, the present invention also encompasses a method of treating a patient in whom ciprofloxacin and pyperidone are co-administered (e. G., At any of the doses given twice a day, 250 mg, 500 mg, or 750 mg) With a reduced dose of about 801 mg / day, or about 800 mg / day, or about 1/3 (from a baseline dose, for example, 1800 mg / day or 2403 mg / day) .

Any of the embodiments, or embodiments, or embodiments described in this disclosure for a method of treatment may be used in such methods for "pypenidone for use" and in the manufacture of medicaments for treatment, The same applies to the use of < / RTI > The use in such an embodiment is further described below. It is further understood that the methods and uses described in this disclosure in connection with the simultaneous administration of ciprofloxacin and pypenidone are equally applicable to ciprofloxacin as well as to ciprofloxacin. Thus, any of the embodiments or embodiments or embodiments described in this disclosure for a method of treatment are equally applicable to "ciprofloxacin for use" in such methods and to the use of ciprofloxacin in the manufacture of a medicament for such methods do. For example, the optional reference to "pyrphenidone for use" applies equally to "ciprofloxacin for use ".

In any of the aspects or embodiments of the disclosure, the patient requires treatment with pypnidone. The effect of ciprofloxacin on increasing firfenidone exposure is applied to any patient who receives treatment with pypnidone, which is independent of the disorder in which the patient requires pypnnidone. In this case, inhibition of CYP1A2 by ciprofloxacin, which increases exposure to pypnidone in a patient, is not the conclusion or outcome of a particular disorder. Any disorder in which the antibiotic ciprofloxacin can be administered for any reason, including the reason that the patient will be administered pypenidone and the patient has not been associated with pypnidone administration during that time, It is considered to be disabled.

For example, the patient may have a fibrotic disorder such as a fibrotic disorder of the lung, kidney, liver, heart, or other organ; Inflammatory disease; Autoimmune disease; Or fibrosis associated with tissue damage, e.g., from infarction, infection, cancer, cirrhosis, and the like. It is known that pypenidone has both anti-fibrosis and anti-inflammatory activity. For example, the patient may be referred to the clinic for the treatment of idiopathic pulmonary fibrosis, pulmonary fibrosis, bronchiolitis obliterans, chronic pulmonary transplant rejection, scleroderma, primary glomerulosclerosis (FSGC) or proliferative glomerulonephritis (MPGN), idiopathic interstitial pneumonia, Atherosclerosis, renal fibrosis disease, fibrotic vascular disease, pulmonary fibrosis disease, pulmonary fibrosis disease, autoimmune pulmonary disease, benign prostatic hypertrophy, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardial fibrosis, musculoskeletal fibrosis, Alzheimer's disease, diabetic retinopathy or skin lesions, lymphatic fibrosis associated with HIV, chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, ; Rheumatic spondylitis; Osteoarthritis; Gout, other arthritic diseases; blood poisoning; Septic shock; Endotoxic shock; Gram-negative sepsis; Toxic shock syndrome; Myofascial pain syndrome (MPS); Sialolithiasis; asthma; Adult respiratory distress syndrome; Inflammatory bowel disease; Crohn's disease; psoriasis; eczema; Ulcerative colitis; Glomerulonephritis; Scleroderma; Chronic thyroiditis; Graves' disease; Ormond disease; Autoimmune gastritis; Myasthenia gravis; Autoimmune hemolytic anemia; Autoimmune neutropenia; Thrombocytopenia; Pancreatic fibrosis; Chronic active hepatitis including liver fibrosis; Acute or chronic renal disease; Renal fibrosis; Diabetic nephropathy; Irritable bowel syndrome; Pyresis; Stenosis; Brain malaria; Stroke or ischemic injury; Neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; Acute or chronic pain; Allergies including allergic rhinitis or allergic conjunctivitis; Cardiac hypertrophy, chronic heart failure; Acute coronary syndrome; cachexy; malaria; leprosy; Rishmaniasis; Lyme disease; Lighter syndrome; Acute synovitis; Muscular degeneration, bursitis; Tendonitis; Hay fever; Ruptured, destroyed or escaped vertebral disc syndrome; Bone calcification; thrombosis; Silicosis; Pulmonary sarcoidosis; Bone resorption diseases such as osteoporosis or multiple myeloma-related bone disorders; Cancer including but not limited to metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, gastric cancer, or non-small cell lung cancer; Graft versus host response; Or autoimmune diseases such as multiple sclerosis, lupus or fibromyalgia; AIDS or other viral diseases such as herpes zoster, herpes simplex I or II, influenza virus, severe acute respiratory syndrome (SARS) or cytomegalovirus; Or breast cancer, including diabetes, proliferative disorders (including benign or malignant hyperplasias), acute myelogenous leukemia, chronic myelogenous leukemia, Kaposi sarcoma, metastatic melanoma, multiple myeloma, metastatic breast carcinoma; Colon rectal carcinoma; Malignant melanoma; Gastric cancer; Non-small cell lung cancer (NSCLC); Bone metastasis; Pain disorders including neuromuscular pain, headache, cancer pain, toothache, or arthritis pain; An angiogenic disorder including solid tumor angiogenesis, intraocular angiogenesis, or infantile hemangioma; A disease associated with a cyclooxygenase or lipoxygenase signaling pathway, including diseases associated with prostaglandin endoperoxide synthase-2 (including edema, fever, analgesia, or pain); Tracheal hypoxia; Thrombin induced platelet aggregation; Or a congenital disease. For example, interstitial lung disease (SSc-ILD) associated with IPF and glomerulonephritis (or systemic sclerosis) has been implicated in the pathology of multiple pathologies, most notably the activation and proliferation of fibroblasts, the expression of fibrotic cytokines and growth factors, (1999) reported that the incidence of interstitial fibrosis was significantly higher than that of the control group (Tzouvelekis et al., 2005; IPF and SSc-ILD also commonly have biomarkers including CCL 18, SP-A, SPD, KL 6, ICAM-1, VCAM 1, CCL 2, YKL-40 and vWF.

Any of the uses or methods described in this disclosure can be used to avoid the possibility of reducing the clearance rate of pypnidolone and / or to avoid the possibility of increasing exposure to pypnidone and / Or to reduce toxicity and / or to improve the stability of pypnidone administration. As described in the examples in the present disclosure, patients who are both administered concurrently with a dose of 750 mg of ciprofloxacin and ciprofloxacin exhibit an increase in exposure to quadrupedone of about 1.8 times Will experience. The use or method described in this disclosure avoids such increased exposure and reduces dose dependent side effects or toxicity associated with pypnidone. For example, when ciprofloxacin is co-administered at a dose of 750 mg, reducing the dose of 2403 mg from about 1/2 to 1/3 will result in an effective pypnidone exposure equivalent to the 2403 mg dose provided in the absence of ciprofloxacin . Similarly, when co-administration of ciprofloxacin at a dose of 750 mg reduces the dose of about 1800 mg to about 1/2 to about 1/3, an effective quercetin exposure equivalent to the 1800 mg dose provided in the absence of ciprofloxacin will be obtained .

In another aspect, the disclosure provides a kit comprising (a) pypenidone, optionally in a container, and (b) a package insert, packaging label, instruction sheet or other labeling that directs or initiates any of the methods or embodiments disclosed herein , A package or a kit.

Figure 1 shows the mean (± SD (SD)) concentration of pyrethroid and 5-carboxy-pyrethrone versus time since dose of ciprofloxacin.

Pirfenidone is an orally active anti-fibrotic agent. The in vitro test results are consistent with a number of other CYPs (such as 1A1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2J2, 3A4, 3A5, 4A11 and 4F2) Which is predominantly metabolized by CYP1A2 (U.S. Patent No. 7,816,383, which is incorporated herein by reference). The data described in this disclosure show that CYP1A2 in vivo accounts for most (70-80%) of the pyrethroid metabolism.

Oral administration of pyupenidone involves the administration of four metabolites: 5-hydroxymethyl-pyrennidone, 5-carboxy-pyrennidone, 4'-hydroxy-pyrpenidone, and 5-carboxy- 5-O-acylglucuronide metabolites are formed. In humans, only pyripenidone and 5-carboxy-pyrpenidone are present in significant amounts in plasma; None of the other metabolites are present in sufficient quantities to allow PK analysis. There is no unique person metabolism.

The data described in this disclosure show that when co-administered with oral doses of 801 mg pyperidone with oral doses of 750 mg ciprofloxacin, approximately 1.8-fold (about 81%) of exposure to pyrpenidone (AUC, ) In the first half of the year. Thus, for example, a patient receiving a daily dose of 2403 mg may be exposed to a level of pyrethroidine equivalent to a dose of about 4325 mg of pyrethroid. In contrast, patients administered a daily dose reduced from 2403 mg to about 1/3 to about 1/2 can be exposed to a level of pyrexenone equivalent to a dose of about 2403 mg. By computer modeling the effect of ciprofloxacin at lower doses, for example, 500 mg or 250 mg oral doses, less effect on the level of pypnnidone, for example approximately 1.5-fold or 1.3-fold increase in exposure, respectively do.

Justice

The term "therapeutically effective amount" as used herein refers to an amount of a compound sufficient to treat, ameliorate or prevent the identified disease or disorder or to exhibit a detectable therapeutic, prophylactic or inhibitory effect. Such effects can be detected, for example, by improvement in clinical disease, or by reduction in symptoms. The precise effective amount of the subject will depend on the weight, size and health of the subject; The nature and extent of the disease; And the therapeutic agent or combination of agents selected for administration. When the drug is approved by the US Food and Drug Administration (FDA), a "therapeutically effective amount" refers to a dose approved by the FDA or its equivalent outpatient department for the treatment of an identified disease or disorder.

As used in this disclosure, "a patient in need of " a treatment with pyperidone is a patient who will benefit from the administration of pyperidone. The patient may be suffering from any disease or condition that may be useful in the treatment of the condition. Firfenidone is a known anti-fibrotic agent, and such disorders include fibrosis disorders such as lung, kidney, liver, heart, or other organs. Other disorders that may benefit from treatment with pypnidone include inflammatory disorders or autoimmune disorders. Another disorder that may benefit from treatment with pypenidone includes diseases that result in fibrosis, or fibrosis associated therewith is associated with symptoms or complications of the disease, such as infarction (tissue necrosis), infection, cancer, cirrhosis, etc. Partially responsible for. For example, the disease or disorder is selected from the group consisting of pulmonary fibrosis, idiopathic pulmonary fibrosis, obstructive bronchiolitis, chronic lung transplant rejection, scleroderma, primary regional segmental glomerulosclerosis (FSGC) or proliferative glomerulonephritis (MPGN), idiopathic interstitial pneumonia, In generalized sclerosis, it is known that in the case of interstitial lung disease, pulmonary fibrosis disease, autoimmune pulmonary disease, benign prostatic hyperplasia, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardial fibrosis, musculoskeletal fibrosis, (COPD), inflammatory pulmonary fibrosis (RA), rheumatoid arthritis (RA), inflammatory bowel disease, inflammatory bowel disease, inflammatory bowel disease, fibromyalgia vascular disease, scleroderma, Hermansky-Pudulak syndrome, neurofibromatosis, Alzheimer's disease, diabetic retinopathy, and / ; Rheumatic spondylitis; Osteoarthritis; Gout, other arthritic diseases; blood poisoning; Septic shock; Endotoxic shock; Gram-negative sepsis; Toxic shock syndrome; Myofascial pain syndrome (MPS); Sialolithiasis; asthma; Adult respiratory distress syndrome; Inflammatory bowel disease; Crohn's disease; psoriasis; eczema; Ulcerative colitis; Glomerulonephritis; Scleroderma; Chronic thyroiditis; Graves' disease; Ormond disease; Autoimmune gastritis; Myasthenia gravis; Autoimmune hemolytic anemia; Autoimmune neutropenia; Thrombocytopenia; Pancreatic fibrosis; Chronic active hepatitis including liver fibrosis; Acute and chronic renal disease; Renal fibrosis; Diabetic nephropathy; Irritable bowel syndrome; Pyrethusis; Stenosis; Brain malaria; Stroke and ischemic injury; Neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; Acute and chronic pain; Allergies including allergic rhinitis and allergic conjunctivitis; Cardiac hypertrophy, chronic heart failure; Acute coronary syndrome; cachexy; malaria; leprosy; Rishmaniasis; Lyme disease; Lighter syndrome; Acute synovitis; Muscular degeneration, bursitis; Tendonitis; Hay fever; Ruptured, destroyed, or escaped vertebral disc syndrome; Bone calcification; thrombosis; Silicosis; Pulmonary sarcoidosis; Bone resorption diseases such as osteoporosis or multiple myeloma-related bone disorders; Cancer including but not limited to metastatic breast carcinoma, colon rectal carcinoma, malignant melanoma, stomach cancer, and non-small cell lung cancer; Graft versus host response; And autoimmune diseases such as multiple sclerosis, lupus and fibromyalgia; AIDS and other viral diseases such as herpes zoster, herpes simplex I or II, influenza virus, severe acute respiratory syndrome (SARS) and cytomegalovirus; And diabetes. In addition, the methods of the embodiments may be used to treat or prevent a proliferative disorder (including both benign and malignant hyperplasias), such as acute myelogenous leukemia, chronic myelogenous leukemia, Kaposi sarcoma, metastatic melanoma, multiple myeloma, metastatic breast carcinoma, ; Colon rectal carcinoma; Malignant melanoma; Gastric cancer; Non-small cell lung cancer (NSCLC); Bone metastasis; Pain disorders including neuromuscular pain, headache, cancer pain, toothache, and arthritis pain; Angiogenic disorders including solid tumor angiogenesis, intra-ocular angiogenesis, and infantile hemangioma; A disease associated with cyclooxygenase and lipoxygenase signaling pathways, including diseases associated with prostaglandin endoperoxide synthase-2 (including edema, fever, analgesia, and pain); Tracheal hypoxia; Thrombin induced platelet aggregation; Or can be used to treat an underlying disease.

A patient in need of "ciprofloxacin therapy" as used in this disclosure is understood to be a patient in need of "antibiotic therapy" or "fluoroquinolone therapy ". Such a patient includes a patient suffering from a bacterial infection.

For CYP enzymes, the FDA generally causes a "potent inhibitor" to cause a> 80% reduction in clearance of the CYP substrate (not limited to the sensitive CYP substrate) or a 5-fold increase in the plasma AUC curve in the clinical evaluation define. FDA recommends that a "moderate inhibitor" be administered at doses ranging from 2 to 5 fold at 50 or 80% reduction in the clearance rate of the sensitive CYP substrate or AUC value when the inhibitor is administered at the shortest administration interval and the highest approved dose in clinical evaluation ≪ / RTI >

Pypennidone  or Ciprofloxacin  Avoidance or interruption of administration

As used in this disclosure, the terms "avoid" and its forms are alternatively considered to have the terms avoid, suspend, inhibit, and refrain from terminology. In some cases, such alternative terms will be equivalent. For example, "to avoid" means "to refrain" ( Merriam-Webster Online Dictionary , 11 ^th ed., 24 November 2009). The term " abort "and its forms, as used in this disclosure, are alternatively considered to have the terms quit, quit, quit, and quit.

The first aspect of the present invention relates to the avoidance of concurrent use of pyperidone in a patient with ciprofloxacin at an equivalent oral dose of 750 mg, for example 750 mg twice daily (1500 mg / day) will be. It is understood that the patient requires treatment with pypnidone and requires antibiotic treatment. In such a method, pyflnidone is avoided during ciprofloxacin administration, or ciprofloxacin is avoided during pyupnidone administration. In a related method, pyflunidone is stopped during ciprofloxacin administration, or ciprofloxacin is stopped during pyflinidone administration. Because of the typically short-term nature of ciprofloxacin therapy, it will usually be more convenient to stop pypnnidone during the time interval that ciprofloxacin is administered. The avoided amount of pyphenidone is, for example, about 1000 to about 4000 mg fiphenidone, or about 1800 mg to about 3600 mg fiphenidone, or about 1800 mg to about 2500 mg fiphenidone, And may range anywhere from about 2600 mg fiphenidone.

In an embodiment of such a method, simultaneous administration of pefpenidone and ciprofloxacin in equivalent doses by different routes is avoided in the method. Three times daily (every 8 hours) Intravenous (iv) administration of ciprofloxacin 400 mg i.v. is considered equivalent to 750 mg administered orally twice daily.

In some embodiments in which pyflnidone is stopped during the co-administration of ciprofloxacin at a dose of 750 mg, for example, 750 mg twice daily, pypnidol may be administered at 1, 2, 3 or 4 hours before or after the time interval in which ciprofloxacin is used , 4, 5 or 6 days or 1 week and / or resumed. In various embodiments, the time interval in which ciprofloxacin is used is, for example, about one week, two weeks, three weeks, four weeks, or one month.

In one embodiment, co-administration of ciprofloxacin at a daily dose of 1500 mg (750 mg twice daily) should be avoided during the treatment with pyperidone due to the possibility of reducing the clearance rate of pyperidone. The dose of ciprofloxacin to be avoided is in the range of dosages (e.g., and without limitation, from about 650 mg to about 850 mg, or from about 1400 mg to about 850 mg, optionally provided twice a day for an overall daily dose of about 1300 mg to about 1700 mg About 700 mg to about 800 mg, optionally dosed twice daily for a total daily dose of 1600 mg). If the 750 mg dose of ciprofloxacin can not be avoided, the total daily dose of pypfenidone should be reduced during co-administration with ciprofloxacin.

Pypennidone  Alternative drug choices for co-administration with therapy

In an embodiment of the method relating to the avoidance of ciprofloxacin to 750 mg, the method comprises administering to the patient a therapeutically effective amount of pypenidone and administering an alternative antibiotic therapy that is not a potent inhibitor of CYP1A2, but not ciprofloxacin . In some instances, the alternative drug is another fluoroquinolone. In some instances, the alternative drug is also not a moderate or potent inhibitor of both CYP1A2 and another CYP selected from the group consisting of CYP2C9, CYP2C19, CYP2D6 and CYP2E1.

In some embodiments, the patient is administered ciprofloxacin at an alternative dose (i.e., less than 750 mg). Thus, in various embodiments, the ciprofloxacin is administered to the patient in a dose of 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, or 500 mg, optionally wherein the dose is administered twice daily (i. E., BID) / RTI >

By notifying the patient or by Pypennidon  Improved dosing

In some embodiments, the disclosure provides a method of treating a patient suffering from pyfemnidone, comprising administering a therapeutically effective amount of pypnnidone to a patient in need of such treatment (e. G., A patient suffering from IPF) and administering to said patient any one, ≪ / RTI > wherein said method comprises administering to said patient a treatment with pypnidone, comprising: < RTI ID = 0.0 >

(a) informing the patient that ciprofloxacin should be avoided or stopped in a dose of 750 mg (or about 650 mg to about 850 mg, or about 700 mg to about 800 mg), optionally given twice a day,

(b) co-administration of pyperidone with ciprofloxacin at a dose of 750 mg (or about 650 mg to about 850 mg, or about 700 mg to about 800 mg), optionally given twice a day, Notify the patient that an effect or adverse response profile may be altered,

(c) the dose of pypfenidone should be reduced in patients treated with ciprofloxacin at a dose of 750 mg (or about 650 mg to about 850 mg, or about 700 mg to about 800 mg), optionally given twice a day To the patient,

(d) co-administering pyrpnidone and ciprofloxacin at 750 mg to inform / inform the patient that an approximately 1.8-fold increase in exposure to pypnidone has occurred,

(e) ciprofloxacin at 750 mg (or about 650 mg to about 850 mg, or about 700 mg to about 800 mg), optionally provided twice-a-day, reduces purpiynidone clearance and / or increases pypnidol exposure Patients should be advised that they should be used with caution in patients receiving pyrennipine.

Administration and dosage adjustment

In various embodiments of the methods described in this disclosure, ciprofloxacin is administered to a patient at a dose equivalent to 750 mg orally, e.g., 750 mg twice a day, or about 650 mg to about 850 mg, or about Ciprofloxacin is administered within a dose range of from 700 mg to about 800 mg, optionally the dose is administered twice a day, and the patient is administered a controlled dose of the reduced (ciprofloxacin-free There is provided a method of co-administration of pyperidnide and ciprofloxacin, wherein the amount of pyperidone administered is reduced compared to the patient, or to a previously administered amount of pyperpnidone in the patient. Preferably, the capacity of the pyrennidone is reduced by about 1/2 to 1/3.

The pyrennidone may be administered in an amount of from about 50 mg to about 4005 mg, or from about 1000 to about 4000 mg fiphenidone, or from about 1800 mg to about 3600 mg fiphenidone, or from about 1800 to about 2500 mg fiphenidone, Can be administered in a total amount of about 2600 mg of pyrethroid. In some embodiments, the amount of pypnnidone administered prior to administration of ciprofloxacin is 2400 mg / day or 2403 mg / day. The dose may be divided into two or three doses per day, or may be administered in a single daily dose. In some embodiments, three pypnidon capsules are administered three times a day, each capsule containing about 267 mg of pyphenidone. The specific amount of the total daily amount of treatment contemplated for the disclosed method is about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 267 mg, about 300 mg, about 350 mg, About 450 mg, about 500 mg, about 534 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 about 1050 mg, about 1068 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1335 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, About 1550 mg, about 1600 mg, about 1602 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1869 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2100 mg, about 2136 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, and about 2403 mg. A reduction of 1/3 to 1/2 can be easily calculated.

The dose of pypenidone may be administered alternatively in a dose measured in mg / kg. The considered mg / kg dose of the disclosed treatment comprises from about 1 mg / kg to about 40 mg / kg. Specific dosage ranges expressed in mg / kg range from about 1 mg / kg to about 30 mg / kg, from about 5 mg / kg to about 30 mg / kg, from about 10 mg / kg to about 40 mg / To about 30 mg / kg, and about 15 mg / kg to about 35 mg / kg. A reduction of 1/3 to 1/2 can be easily calculated.

In one embodiment, the dose of pyrennidone is ingested with the food. In another embodiment, the patient is instructed to administer a dose of pyperidone with the food.

In some embodiments, the capacity is reduced by about 1/2 to 1/3 (e.g., 50% to 67%). In certain embodiments, the dose is reduced by about 1/3 compared to the dose previously administered. In a further embodiment, the dose is about 40%, 50%, 60%, 70% or more of the previously administered dose, or about 40% to about 70% To 50% to about 70%.

For example, when the patient is administered about 2403 mg / day furfenidone, the furfenidone dose ranges from about 1200 mg / day to about 1700 mg / day, or about 1400 mg / day for concurrent use of ciprofloxacin To about 1650 mg / day.

As another example, when the patient is administered about 1800 mg / day furfenidone, the furfenidone dose ranges from about 900 mg / day to about 1300 mg / day, or from about 1000 mg / day to about 1000 mg / day during ciprofloxacin co- To about 1250 mg / day.

In such embodiments involving a reduction in dose, for example, as soon as ciprofloxacin is discontinued in a dose of 750 mg or more (or about 650 mg to about 850 mg, or about 700 mg to about 800 mg) twice a day, The dose is titrated to the recommended maximum dose for the patient. In some embodiments, the capacity of pyperidone is readjusted to a capacity of 2400 or greater than 2403 mg / day.

As noted above, in any of the implementations described in this disclosure, which include, but are not limited to, interruption or capacity reduction, packaging and kit, and / or manufacturing or packaging methods of pyrenendin, Methods, packages, kits, devices, warnings, interruptions, or dosage adjustments may be applied not only to oral doses of 750 mg ciprofloxacin administered twice a day, for example, but also to any other equivalent doses administered by other routes . Intravenous (iv) administration of ciprofloxacin 400 mg i.v. three times daily (every 8 hours) is considered equivalent to 750 mg administered orally twice daily.

package, Kit , Packaging method, and delivery method

In another aspect, a package or kit is provided that includes a package insert, package label, instruction sheet, or other labeling, optionally including a pyrethroid in the container, and instructions or instructions for any of the methods disclosed herein.

The package insert, package label, instructions or other labeling may be prepared by administering pypenidone at a dose of, for example, 2400 mg or 2403 mg per day, such that the pypenidone is required, for example IPF or any other And may further include instructions for treating a patient suffering from a disorder or disease.

In a related aspect, the disclosure provides a method of manufacturing or packaging a pyrennydon drug, optionally packaging the pyrennydon in a container, with a package insert or package label or instructions for any of the methods disclosed herein do.

In some embodiments, a method of treating a patient in need of pypnnidone is provided, including providing, selling, or delivering any of the kits disclosed herein to a hospital, physician, or patient.

In some embodiments, a patient in need of ciprofloxacin at 750 mg, including providing or delivering a kit comprising ciprofloxacin to a hospital, physician or patient with a package insert or package label or instruction for any of the methods disclosed herein Is provided.

The present disclosure will be more fully understood by reference to the following examples which illustrate exemplary implementations of the present disclosure. However, the following examples should not be construed as limiting the scope of this disclosure. All references cited throughout this disclosure are hereby expressly incorporated by reference.

Examples of aspects and embodiments of the present invention

1. Oral doses of 750 mg, or oral doses of 650 mg to 850 mg, or oral doses of 700 mg to 800 mg, eg, 750 mg (1500 mg / day) twice daily, During the simultaneous administration of ciprofloxacin at an intravenous (iv) dose of 400 mg iv per dose, the dose of pyphenidone to be administered to the patient is reduced by about 1/2 to about 1/3, Pirfenidone for use in treating patients who need treatment with pyrennydon.

2a. Pyrennidone is administered to a patient in a therapeutically effective amount, orally orally at an oral dose of 700 mg or more, or at an oral dose of 750 mg or more, for example, at an oral dose of 750 mg or more (1500 mg or more per day) Or to avoid simultaneous administration of ciprofloxacin at an intravenous (iv) dose of 400 mg or more iv three times per day.

2b. Ciprofloxacin is administered at an oral dose of 700 mg or more, or an oral dosage of 750 mg or more, for example, at an oral dose of 750 mg or more (1500 mg or more per day) twice or three times per day Pypnnidone for use in treating a patient in need of pypnnidone treatment, including a time interval during which pypnnidone is avoided during administration in intravenous (iv) doses of iv over 400 mg. According to this embodiment, it is understood that once the ciprofloxacin is stopped, the pypennidone is resumed.

3. The method of claim 1, wherein during the administration of ciprofloxacin, the pyrethroid dose is reduced from about 2403 mg / day to a dose in the range of about 1400 mg / day to about 1650 mg / day, optionally to 1602 mg / Penny Don.

4. The method of claim 1, wherein during the administration of ciprofloxacin, the pyrethroid dose is reduced from about 1800 mg / day to a dose in the range of about 1000 mg / day to about 1250 mg / day, optionally to 1200 mg / Penny Don.

5. Use of pyperpinidone for use according to any one of the above embodiments 1-4, wherein pyperidone for use is to avoid the possibility of reducing pyrethranid clearance or increasing the exposure to pyrethrone .

6. The pypnnidone for use according to any one of embodiments 1 to 5 above, wherein the total daily dose of pypenidone is administered to the patient in divided doses three times per day, with the food.

7. The pypnnidone for use according to any one of the preceding embodiments 1-6, wherein the pypnidone is administered in unit dosage form, which is a capsule or tablet.

8. Firfenidone for use according to embodiment 7 above, wherein the amount of furfenidone in the unit dosage form is 200 mg or 267 mg.

9. Pirfenidone for use in Embodiment 3 above, wherein 534 mg of pypenidone is administered to the patient three times per day during the ciprofloxacin co-administration.

10. The pypnnidone for use according to embodiment 3 above, wherein the pyflunidone is administered in a total daily dose of 1602 mg during ciprofloxacin co-administration.

11. The pypnnidone for use as in embodiment 3 above, wherein the pyflunidone is administered in a total daily dose of about 1600 mg during ciprofloxacin co-administration.

12. Pirfenidone for use according to any of the preceding embodiments 1 to 11, wherein the patient is suffering from idiopathic pulmonary fibrosis (IPF).

13. The pypnnidone for use according to any of the preceding embodiments 1 to 11, wherein the patient is suffering from a fibrosing disorder, an inflammatory disorder, or an autoimmune disorder.

14. The method according to claim 1, wherein the patient is at least one of the following: epilepsy in idiopathic pulmonary fibrosis, pulmonary fibrosis, bronchiolitis obliterans, chronic lung transplant rejection, scleroderma, primary glomerular sclerosis (FSGC) or proliferative glomerulonephritis (MPGN) Atherosclerosis, renal fibrosis disease, fibrotic vascular disease, pulmonary fibrosis disease, pulmonary fibrosis disease, autoimmune pulmonary disease, benign prostatic hyperplasia, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardial fibrosis, musculoskeletal fibrosis, Neurofibromatosis, Alzheimer's disease, diabetic retinopathy, skin lesions, lymphadenopathy associated with HIV, chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis, rheumatoid arthritis; Rheumatic spondylitis; Osteoarthritis; Gout, other arthritic diseases; blood poisoning; Septic shock; Endotoxic shock; Gram-negative sepsis; Toxic shock syndrome; Myofascial pain syndrome (MPS); Sialolithiasis; asthma; Adult respiratory distress syndrome; Inflammatory bowel disease; Crohn's disease; psoriasis; eczema; Ulcerative colitis; Glomerulonephritis; Scleroderma; Chronic thyroiditis; Graves' disease; Ormond disease; Autoimmune gastritis; Myasthenia gravis; Autoimmune hemolytic anemia; Autoimmune neutropenia; Thrombocytopenia; Pancreatic fibrosis; Chronic active hepatitis including liver fibrosis; Acute or chronic renal disease; Renal fibrosis; Diabetic nephropathy; Irritable bowel syndrome; Pyrethusis; Stenosis; Brain malaria; Stroke or ischemic injury; Neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; Acute or chronic pain; Allergies including allergic rhinitis or allergic conjunctivitis; Cardiac hypertrophy, chronic heart failure; Acute coronary syndrome; cachexy; malaria; leprosy; Rishmaniasis; Lyme disease; Lighter syndrome; Acute synovitis; Muscular degeneration, bursitis; Tendonitis; Hay fever; Ruptured, destroyed, or escaped vertebral disc syndrome; Bone calcification; thrombosis; Silicosis; Pulmonary sarcoidosis; Bone resorption diseases such as osteoporosis or multiple myeloma-related bone disorders; Cancer including but not limited to metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, gastric cancer, or non-small cell lung cancer; Graft versus host response; Or autoimmune diseases such as multiple sclerosis, lupus or fibromyalgia; AIDS or other viral diseases such as herpes zoster, herpes simplex I or II, influenza virus, severe acute respiratory syndrome (SARS) or cytomegalovirus; Or breast cancer, including diabetes, proliferative disorders (including benign or malignant hyperplasias), acute myelogenous leukemia, chronic myelogenous leukemia, Kaposi sarcoma, metastatic melanoma, multiple myeloma, metastatic breast carcinoma; Colon rectal carcinoma; Malignant melanoma; Gastric cancer; Non-small cell lung cancer (NSCLC); Bone metastasis; Pain disorders including neuromuscular pain, headache, cancer pain, toothache, or arthritis pain; An angiogenic disorder including solid tumor angiogenesis, intraocular angiogenesis, or infantile hemangioma; A disease associated with a cyclooxygenase or lipoxygenase signaling pathway, including diseases associated with prostaglandin endoperoxide synthase-2 (including edema, fever, analgesia, or pain); Tracheal hypoxia; Thrombin induced platelet aggregation; Or pyoderma thaliana for use according to any one of the above Embodiments 1 to 11, suffering from a disease selected from a malignant disease or a benign disease.

15. The method of claim 1, wherein during the simultaneous administration of fiphenidone, the dose of ciprofloxacin is 750 mg oral dose, or 650 mg to 850 mg oral dose, or 700 mg to 800 mg, day), or intravenous (iv) dose of 400 mg iv three times per day, and the dose of pyrennidone for administration to the patient is about 1/2 to about 1/3, preferably 1 / Ciprofloxacin for use in the treatment of patients requiring ciprofloxacin therapy, for example, having a bacterial infection.

16. Ciprofloxacin is administered at oral doses of 700 mg or more, or oral doses of 750 mg or more, eg, oral doses of 750 mg or more (1500 mg or more per day) twice daily or 400 mg or more of iv (Iv) avoiding ciprofloxacin during simultaneous administration of ciprofloxacin, or (b) avoiding ciprofloxacin during simultaneous administration of pypnidol, in a patient in need of ciprofloxacin therapy Ciprofloxacin for use.

17. The use of ciprofloxacin as defined in claim 1, wherein the ciprofloxacin is administered at an oral dose of 700 mg or more, or an oral dosage of 750 mg or more, for example, at an oral dose of 750 mg or more (1500 mg or more per day) Ciprofloxacin for use in treating a patient in need of ciprofloxacin treatment, wherein said ciprofloxacin is administered over a time interval during which pypnnidone is avoided during administration in an intravenous (iv) dose of 400 mg or more. According to this embodiment, it is understood that once the ciprofloxacin is stopped, the pypennidone is resumed.

18. The use of ciprofloxacin for the use of Embodiment 15, wherein the fiphenidone dose is reduced from about 2403 mg / day to a dose in the range of about 1400 mg / day to about 1650 mg / day, optionally to 1602 mg / day during ciprofloxacin administration .

19. The use of ciprofloxacin for the use of Embodiment 15 above, wherein the fiphenidone dose is reduced from about 1800 mg / day to a dose in the range of from about 1000 mg / day to about 1250 mg / day, optionally to 1200 mg / day during ciprofloxacin administration .

20. Ciprofloxacin for use as in embodiment 16 or 17 above, for the purpose of avoiding the possibility of pypennidone to reduce the clearance rate of pypenidone or to increase exposure to pypnnidone.

21. Ciprofloxacin for use as in embodiment 15 above, wherein 534 mg of pypenidone is administered to the patient three times per day during the ciprofloxacin co-administration.

22. Ciprofloxacin for use as in embodiment 15, wherein the pyflunidone is administered in a total daily dose of 1602 mg during ciprofloxacin co-administration.

23. Ciprofloxacin for use as in embodiment 15, wherein the pyflunidone is administered in a total daily dose of about 1600 mg during ciprofloxacin co-administration.

24. Ciprofloxacin for use according to any one of the embodiments 15-23, wherein the patient is suffering from idiopathic pulmonary fibrosis (IPF).

25. The pypnnidone for use according to any one of embodiments 15-23, wherein the patient is suffering from a fibrosing disorder, an inflammatory disorder, or an autoimmune disorder.

26. The method of claim 1, wherein the patient is at least one of epilepsy (s) in idiopathic pulmonary fibrosis, pulmonary fibrosis, obstructive bronchiolitis, chronic pulmonary transplant rejection, scleroderma, primary glomerular sclerosis (FSGC) or proliferative glomerulonephritis (MPGN) Atherosclerosis, renal fibrosis disease, fibrotic vascular disease, pulmonary fibrosis disease, pulmonary fibrosis disease, autoimmune pulmonary disease, benign prostatic hyperplasia, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardial fibrosis, musculoskeletal fibrosis, Neurofibromatosis, Alzheimer's disease, diabetic retinopathy, skin lesions, lymphadenopathy associated with HIV, chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis, rheumatoid arthritis; Rheumatic spondylitis; Osteoarthritis; Gout, other arthritic diseases; blood poisoning; Septic shock; Endotoxic shock; Gram-negative sepsis; Toxic shock syndrome; Myofascial pain syndrome (MPS); Sialolithiasis; asthma; Adult respiratory distress syndrome; Inflammatory bowel disease; Crohn's disease; psoriasis; eczema; Ulcerative colitis; Glomerulonephritis; Scleroderma; Chronic thyroiditis; Graves' disease; Ormond disease; Autoimmune gastritis; Myasthenia gravis; Autoimmune hemolytic anemia; Autoimmune neutropenia; Thrombocytopenia; Pancreatic fibrosis; Chronic active hepatitis including liver fibrosis; Acute or chronic renal disease; Renal fibrosis; Diabetic nephropathy; Irritable bowel syndrome; Pyrethusis; Stenosis; Brain malaria; Stroke or ischemic injury; Neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; Acute or chronic pain; Allergies including allergic rhinitis or allergic conjunctivitis; Cardiac hypertrophy, chronic heart failure; Acute coronary syndrome; cachexy; malaria; leprosy; Rishmaniasis; Lyme disease; Lighter syndrome; Acute synovitis; Muscular degeneration, bursitis; Tendonitis; Hay fever; Ruptured, destroyed, or escaped vertebral disc syndrome; Bone calcification; thrombosis; Silicosis; Pulmonary sarcoidosis; Bone resorption diseases such as osteoporosis or multiple myeloma-related bone disorders; Cancer including but not limited to metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, gastric cancer, or non-small cell lung cancer; Graft versus host response; Or autoimmune diseases such as multiple sclerosis, lupus or fibromyalgia; AIDS or other viral diseases such as herpes zoster, herpes simplex I or II, influenza virus, severe acute respiratory syndrome (SARS) or cytomegalovirus; Or breast cancer, including diabetes, proliferative disorders (including benign or malignant hyperplasias), acute myelogenous leukemia, chronic myelogenous leukemia, Kaposi sarcoma, metastatic melanoma, multiple myeloma, metastatic breast carcinoma; Colon rectal carcinoma; Malignant melanoma; Gastric cancer; Non-small cell lung cancer (NSCLC); Bone metastasis; Pain disorders including neuromuscular pain, headache, cancer pain, toothache, or arthritis pain; An angiogenic disorder including solid tumor angiogenesis, intraocular angiogenesis, or infantile hemangioma; A disease associated with a cyclooxygenase or lipoxygenase signaling pathway, including diseases associated with prostaglandin endoperoxide synthase-2 (including edema, fever, analgesia, or pain); Tracheal hypoxia; Thrombin induced platelet aggregation; Or a prophylactic < RTI ID = 0.0 > disease. ≪ / RTI >

27. The use of pypnnidone in a total daily dose reduced from about 1/2 to about 1/3 during simultaneous use of ciprofloxacin at a dose of about 650 mg to about 850 mg twice daily.

28. Pypennidone for use in a total daily dose reduced by about 1/2 to about 1/3 during the simultaneous use of ciprofloxacin at a dosage of about 650 mg to about 850 mg twice daily.

29. The use of Embodiment 27 above, wherein the concurrent use of ciprofloxacin is at a dose of about 700 mg to about 800 mg twice a day, or pypennidone for use as in Embodiment 28 above.

30. The use of Embodiment 27 above, wherein the concurrent use of ciprofloxacin is at a dose of about 750 mg (1500 mg / day) twice daily, or pypennidone for use as in Embodiment 28 above.

31. The use of pyrepenidone for use or use according to any one of embodiments 27 to 30, wherein the total daily dose of pypenidone is reduced from about 2403 mg / day to about 1400 mg / day to about 1650 mg / day. .

32. The pyplanidone for use or use according to any one of embodiments 27 to 30 above, wherein the total daily dose of pypenidone is reduced from about 2403 mg / day to about 1602 mg / day.

33. The pyplanidone for use or use according to any one of embodiments 27 to 30 above, wherein the total daily dose of pypenidone is reduced from about 1800 mg / day to about 1000 mg / day to 1250 mg / day.

34. The pyplanidone for use or use according to any one of embodiments 27 to 30, wherein the total daily dose of pypenidone is reduced from about 1800 mg / day to about 1200 mg / day.

35. A pyphenidone for use or use according to any one of the above Examples 27 to 34, for the purpose of avoiding the possibility of reducing the clearance rate of pypennidone or increasing the exposure to pypnidone.

36. The pyplanidone for use or use according to any one of embodiments 27 to 35 above, wherein the total daily dose of pypenidone is to be administered in divided doses three times daily with the food.

37. The pyplanidone for use or use according to any one of the above Examples 27 to 36, wherein the pyphenidone is in one or more unit dosage forms which are capsules or tablets.

38. The pypnnidone for use or use according to embodiment 37 above, wherein the amount of pyphenidone in each of the one or more unit dosage forms is 200 mg or 267 mg.

39. The pypnnidone for use or use according to embodiment 37 above, wherein the pypenidone is present in 267 mg capsules.

40. Two unit dosage forms for administration three times per day with food. The amount of pyrethroids for use or use of any of the above Examples 27 to 32 and 35 to 39, wherein the amount of pyrethrone hydrate is 534 mg. .

41. The pyplanidone for use or use according to any one of embodiments 27 to 31 and 35 to 40 above, wherein the total daily dose of pypenidone is reduced to 1602 mg / day.

42. The pyplanidone for use or use according to any one of embodiments 27 to 31 and 35 to 40 above, wherein the total daily dose of pypenidone is reduced to about 1600 mg / day.

43. Pirfenidone for use or use of any one of the above Examples 27 to 42 in a patient suffering from idiopathic pulmonary fibrosis (IPF).

44. A pypnnidone for the use or use of any one of the above Examples 27 to 42 in a patient suffering from a fibrosing disorder, an inflammatory disorder, or an autoimmune disorder.

45. Interstitial pulmonary disease (COPD) in idiopathic pulmonary fibrosis, pulmonary fibrosis, obstructive bronchiolitis, chronic lung transplant rejection, scleroderma, primary glomerular glomerulosclerosis (FSGC) or proliferative glomerulonephritis (MPGN), idiopathic interstitial pneumonia, , Pulmonary fibrosis disease, autoimmune pulmonary disease, benign prostatic hyperplasia, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardial fibrosis, musculoskeletal fibrosis, postoperative adhesions, liver cirrhosis, renal fibrosis disease, fibrovascular disease, Alzheimer's disease, diabetic retinopathy, or skin lesions, lymphadenopathy associated with HIV, chronic obstructive pulmonary disease (COPD), inflammatory pulmonary fibrosis, rheumatoid arthritis; Rheumatic spondylitis; Osteoarthritis; Gout, other arthritic diseases; blood poisoning; Septic shock; Endotoxic shock; Gram-negative sepsis; Toxic shock syndrome; Myofascial pain syndrome (MPS); Sialolithiasis; asthma; Adult respiratory distress syndrome; Inflammatory bowel disease; Crohn's disease; psoriasis; eczema; Ulcerative colitis; Glomerulonephritis; Scleroderma; Chronic thyroiditis; Graves' disease; Ormond disease; Autoimmune gastritis; Myasthenia gravis; Autoimmune hemolytic anemia; Autoimmune neutropenia; Thrombocytopenia; Pancreatic fibrosis; Chronic active hepatitis including liver fibrosis; Acute or chronic renal disease; Renal fibrosis; Diabetic nephropathy; Irritable bowel syndrome; Pyrethusis; Stenosis; Brain malaria; Stroke or ischemic injury; Neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; Acute or chronic pain; Allergies including allergic rhinitis or allergic conjunctivitis; Cardiac hypertrophy, chronic heart failure; Acute coronary syndrome; cachexy; malaria; leprosy; Rishmaniasis; Lyme disease; Lighter syndrome; Acute synovitis; Muscular degeneration, bursitis; Tendonitis; Hay fever; Ruptured, destroyed, or escaped vertebral disc syndrome; Bone calcification; thrombosis; Silicosis; Pulmonary sarcoidosis; Bone resorption diseases such as osteoporosis or multiple myeloma-related bone disorders; Cancer including but not limited to metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, gastric cancer, or non-small cell lung cancer; Graft versus host response; Or autoimmune diseases such as multiple sclerosis, lupus or fibromyalgia; AIDS or other viral diseases such as herpes zoster, herpes simplex I or II, influenza virus, severe acute respiratory syndrome (SARS) or cytomegalovirus; Or breast cancer, including diabetes, proliferative disorders (including benign or malignant hyperplasias), acute myelogenous leukemia, chronic myelogenous leukemia, Kaposi sarcoma, metastatic melanoma, multiple myeloma, metastatic breast carcinoma; Colon rectal carcinoma; Malignant melanoma; Gastric cancer; Non-small cell lung cancer (NSCLC); Bone metastasis; Pain disorders including neuromuscular pain, headache, cancer pain, toothache, or arthritis pain; An angiogenic disorder including solid tumor angiogenesis, intraocular angiogenesis, or infantile hemangioma; A disease associated with a cyclooxygenase or lipoxygenase signaling pathway, including diseases associated with prostaglandin endoperoxide synthase-2 (including edema, fever, analgesia, or pain); Tracheal hypoxia; Thrombin induced platelet aggregation; Or pyritinidone for use or use according to any one of the above Examples 27 to 42 in a patient suffering from a disease selected from the group consisting of:

46. Use of pyrenpyridone in a total daily dose of 1602 mg / day for the treatment of fibrosing disorders in patients receiving ciprofloxacin concurrently at a dose of 750 mg three times daily.

47. Pirfenidone for use in a total daily dose of 1602 mg / day for the treatment of fibrosing disorders in patients receiving ciprofloxacin concurrently at a dose of 750 mg three times daily.

48. Pypennidone for use or use of pypnnidone according to any of the preceding embodiments 46 and 47, adapted to be administered in one or more unit dosage forms three times per day.

49. The use or use of pypnnidone according to embodiment 48 above, wherein the unit dosage form is 267 mg capsules.

50. The use of pyrepenedon according to any one of the above embodiments 46 to 49, wherein the fibrotic disorder is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), bronchiolitis obliterans (BO), renal fibrosis, Penny Don.

51. A pharmaceutical composition comprising 1602 mg of pyrepanidol and a pharmaceutically acceptable excipient in one or more unit dosage forms for use in treating a fibrotic disorder in a patient in whom ciprofloxacin is co-administered at a dosage of 750 mg twice daily, .

52. The pharmaceutical composition according to embodiment 51 above, wherein the fibrosing disorder is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), bronchiolitis obliterans (BO), renal fibrosis and scleroderma.

53. A pharmaceutical composition comprising (a) pyphenidon, optionally in a container, and (b) a package insert, package label, instructions or other labeling for a pyperpinidone for use or use according to any one of the above embodiments 27 to 52 , Package or kit.

Example

Example  One

Pypennidon Pharmacokinetics  And safety Ciprofloxacin  Open-label Phase 1 study to measure impact

Step 1, open-label cross-over studies were conducted to investigate the effects of ciprofloxacin administration on pharmacokinetics and safety of firfenidone. Twenty seven healthy subjects were enrolled in the study. Subjects were enrolled in a Phase 1 Clinical Center and were eligible for up to 28 days prior to dosing. After meeting the inclusion / exclusion criteria, subjects participated in the first day clinic, which was prepared to receive a single dose of 801 mg of fiphenidone with food on the first day. From the subjects, pharmacokinetic analysis of furfenidone and its major metabolite, 5-carboxy-pyphenidone, at various times before administration (blood PK only) and 32 hours (h) Blood and urine samples were collected. After the safety evaluation and collection of the final PK samples, the subjects were sent out from the clinic for two days. On days 2-7, subjects were administered a moderate CYP1A2 inhibitor, ciprofloxacin (self-administered while outside the clinic). On days 2 to 6, subjects completed a diary card that recorded ciprofloxacin dose and any adverse experience (AE) experienced. On the fifth day, subjects participated in the clinic again. On day 6, each subject received a single dose of 801 mg of pypenidone in addition to ciprofloxacin. Blood and urine samples were collected for pypenidone and 5-carboxy-pyperidone PK analysis using the same sampling schedule as Day 1. All subjects were discharged on day 7 after safety evaluation and final PK sample collection. After the subjects were released from the clinic, they conducted follow-up calls for approximately 24 hours (day 8).

Ciprofloxacin inhibits CYP1A2 activity [Karjalainen et al., Basic and Clinical Pharmacology & Toxicology 103 : 157-165 (2008)]. The selected dose of ciprofloxacin (twice daily [BID] 750 mg) was typically higher than the prescribed dose of 250 to 500 mg BID, which was selected to maximize the CYP1A2 inhibitory effect of this drug. The duration of ciprofloxacin concurrent administration and ciprofloxacin administration prior to subsequent PK sampling was 4 days. Considering the short half-life of ciprofloxacin (approximately 3 to 5 hours), the steady-state will be well within the 4 day administration period.

The inclusion criteria included:

Ages 18 to 55 years old (inclusive).

Body mass index (BMI) of 18 kg / ㎡ to 40 kg / ㎡ (inclusive).

ㆍ Not pregnant.

ㆍ From the 48th hour before the dose through the final study visit.

Good medical condition, as indicated by medical records, physical examination, vital signs, electrocardiogram (ECG) and clinical laboratory evaluation.

The non-inclusion conditions included:

History of active cardiovascular, respiratory, liver, kidney, gastrointestinal, endocrine or neurological disorders that can alter the absorption, metabolism or excretion of the drug.

Clinically significant disease history within 30 days prior to the initial administration of study drug.

Previous adverse experiences (AE), allergic reactions, or sensitivity to ciprofloxacin.

Consumption of grapefruit, grapefruit juice, or any fruit juice within 48 hours prior to the first administration of the study drug.

Use of products containing alcohol, caffeine, or xanthine within 48 hours prior to administration.

Consumption of mustard and vegetables (ie, broccoli, drop cabbage, kale, etc.) or char-grilled meat within 48 hours prior to dosing.

The use of tobacco products within the first 3 months of study drug administration.

Use of co-medications (including non-prescription medications).

administration

801 mg are pireu penny with money one day and the sixth day in the morning food orally administered (3 × given in 267 mg capsules).

Ciprofloxacin 750 mg tablets orally administered as follows:

ㆍ Day 2: 750 mg in the evening.

3 to 6 days: 750 mg twice a day (BID).

ㆍ Day 7: 750 mg in the morning.

750 mg BID dose of ciprofloxacin was chosen to most likely cause moderate and relatively selective inhibition of CYP1A2 activity [Karjalainen et al., Basic and Clinical Pharmacology & Toxicology 103 : 157-165 (2008)]. This dose, although approved for use in severe infections, is higher than the more commonly prescribed dose of 500 mg BID, providing a "worst case" scenario for selective intermediate CYP1A2 inhibition.

Duration of treatment : 1 day and 6 days pypennidone; Ciprofloxacin for 2 to 7 days.

Statistical method

Pharmacokinetics : The PK group was administered both doses of pyrifnidone (1 and 6 days), had at least 4 serum PK samples, and was administered on days 2, 3 and 4 Protocol) doses of ciprofloxacin at doses of 5, 6, and 7 days, and all doses of ciprofloxacin at all doses (3750 mg total) on days 5, 6, and 7 were administered.

Both the non-compartmentalization method and the previously obtained population PK (i.e., compartmental) model were used to analyze serum concentration-time data and characterize individual subject PK parameters. Was tested using the pireu penny money and its main metabolite, 5-carboxy pireu penny criteria allowed for bioequivalence (bioequivalence) for the effect of co-administration of ciprofloxacin for money AUC _{0 -∞} and C _max for paired data .

Safety : The safety group was defined as subjects receiving randomized doses of pyfenidol or ciprofloxacin.

result

Baseline characteristics: The study group consisted of 17 males and 10 females in the age range of 18 to 49 years (median 24 years). The study group consisted mainly of whites (21 subjects, 77.8%) and two (7.4%) American Indians / Alaska Natives, Asians, and Black / African-Americans respectively. BMI ranged from 18.6 to 32.6 kg / m 2 (median 24.4 kg / m 2). The medical records were usually plain, and no subjects were given any concurrent medications at baseline.

Pharmacokinetic Results : For pyperidone co-administered with ciprofloxacin, the difference in C _max and T _max (time to peak plasma concentration) between 1/2 and 6/7 days was appropriate; The geometric mean C max was approximately 20% higher at 6/7 day, while the median T _max was the same in both cases (2 hours). The apparent terminal elimination half-life for pypenidone was slightly prolonged on day 6/7, but remained relatively short (4.1 hour geometric mean for 2.4 hours on day 1). The most prominent effect of ciprofloxacin co-administration on firfenidone was confirmed using co-administration of ciprofloxacin on day 6/7, approximately 78% higher AUCo _-∞ compared to 1/2 days.

For 5-carboxy-pyrennidone, differences in C _max and T _max were also appropriate when comparing 1/2 and 6/7; The trend for C _max was reversed (40% lower at 6/7 day ciprofloxacin co-administration) and the median T _max estimates were also the same. The trend in apparent terminal loss half-life was similar to that found for pypenidone; Slightly extended on day 6/7, but remained relatively short (geometric mean of 4.0 hours versus 2.6 hours on day 1). The effect of ciprofloxacin co-administration on 5-carboxy-pyphenidone AUC _{0- ∞} was less pronounced; The geometric mean of 6/7 days was only 7.7% lower than that of the 1/2 day.

Based on bioequivalence criteria, the co-administration of pypnidone and ciprofloxacin resulted in a statistically significant increase in AUC _0-∞ (geometric mean ratio [GMR] of 1.81 [1.70 to 1.93] [90% confidence interval (CI) ]). The magnitude of the effect (an increase of less than 2-fold in the exposure) indicates that cyflocasin will be classified as a moderate inhibitor of the purpiynidone clearance at a dose of 750 mg (EMEA 2010; US FDA 2006). The effect on firfenidone C _max was more appropriate but still statistically significant (1.23 [1.14-1.31] GMR [90% CI]). There was no statistically significant effect of ciprofloxacin co-administration on 5-carboxy-pyphenidone AUC _{0 -∞} (0.96 [0.92-1.00] GMR [90% CI]). However, the delay in purpennidone clearance resulted in a statistically significant decrease in the 5-carboxy-pypnidone C _max (GMR [90% CI]) of 0.62 [0.57-0.66].

Safety results : An adverse event (TEAE) from 25 treatments was reported for 9 subjects (33.3%). In the majority of these 9 subjects, the severest AE was moderate (7 subjects, 25.9%); At the same time, the severest AE reported for two subjects (7.4%) was moderate. The moderate AE of both was considered unrelated to the study drug.

For the six subjects, the most potent fulpennid association for AE evaluated by the researchers was probably associated with pypnidone. One subject experienced an AE that was considered to be related to pyperidone on day 1 (only firfenidone was administered); The remaining 5 subjects experienced AE only on day 6 (co-administered with ciprofloxacin).

conclusion

The ciprofloxacin 750 mg BID in the case of administration of the (medium-high, yet relatively selective inhibitor of CYP1A2 capacity), statistically significant increase in both AUC _{0 -∞} of pireu penny money and C _max than was observed for 5 days. However, the magnitude of the effect was relatively modest: a co-administration of ciprofloxacin resulted in an 81% increase (i.e., less than 2-fold) and a 23% increase in pypenidone C _max for AUC _{0 -∞} 1).

[Table 1] Statistical summary for plasma pharmacokinetic parameters classified by study date (N = 27)

[Table 2] Effect of co-administration of ciprofloxacin on pypenidone (N = 27)

Example  2

In vitro  - In vivo  calculation( IVIVE ) Research

In vitro data have been found useful in simulating in vivo drug-drug interactions [Ito et al., Drug Metabolism and Disposition 33 (6): 837-844 (2005); Karjalainen et al ., Basic and Clinical Pharmacology & Toxicology 103: 157-165 (2008); McGinnity et al., Drug Metabolism and Disposition 36 (6): 1126-1134 (2008); Zhang et al., Acta Pharmacol Sin 29 (12): 1507-1514 (2008)). In short, the above procedure is based on in vitro knowledge about the characteristics of potential inhibitors [IC ₅₀ values for various cytochrome P450 (CYP) enzymes] in vitro knowledge (the fraction metabolized by various CYP enzymes) on the metabolic pathway of the substrate ≪ / RTI > By so-called in vitro-in vivo estimation (IVIVE), it is possible to model the value of the predicted change in the secondary substrate drug AUC (? AUC) for drug-drug interactions (McGinnity et al., Drug Metabolism and Disposition 36 (6): 1126-1134 (2008)). The results of the IVIVE simulations conducted on pyperidyne are presented below and compared with the actual data from Example 1.

Ciprofloxacin - Pypennidone IVIVE  Simulation

The predicted ratios of pypenidone AUC were simulated prior to and during administration of ciprofloxacin, using the results of in vitro data on ciprofloxacin and the hypothetical combination of the pyperidone fraction metabolized by various CYP enzymes. This was done using the following equation (obtained from McGinnity et al., Drug Metabolism and Disposition 36 (6): 1126-1134 (2008)):

Equation 1

Wherein, [I] _{in, u} are inhibitors introduced to the liver and a free drug concentration (e.g., ciprofloxacin), K _ix is a K _i for ciprofloxacin for CYP provided, fm _x is metabolized by CYP enzymes Is the fraction of the substrate drug (pyrphenidone). [I] _in, estimates for the _u and K _ix is described in [. McGinnity et al, Drug Metabolism and Disposition 36 (6): 1126-1134 (2008)] to test the other hand, there is an estimate of _x fm obtained from in vitro Based on data-based possible scenarios of pyperidine.

In these simulations, the predicted ΔAUC for pypenidone was simulated with co-administered ciprofloxacin, using a hypothetical combination of pypermine donated by various CYP enzymes. Estimates for [I] _{in, u} and K _ix can be found in Zhang et al. , Acta Pharmacol Sin 29 (12): 1507-1514 (2008)). The simulated results for the "baseline case" and ciprofloxacin doses of 750 mg BID using the higher metabolized fraction are shown in Table 3 below.

Table 3: Predicted effects of 750 mg dose of ciprofloxacin co-administration on pyperidone PK under several hypothetical scenarios for the pyperidone fraction metabolized by CYP1A2

Simulation results for ciprofloxacin doses of 250 or 500 mg BID using 48% and 75% fm _1A2 estimates are presented in Table 4 below; The only difference in the estimates for these simulations is the lower [I] _{in, u} due to the lower capacity. This lower dose of ciprofloxacin would be expected to result in less effect on the clearance of pyperidone. The predicted mean fold-change in the pyupnemydon AUC was 1.20 for a dose of 250 mg BID and 500 mg BID, respectively, according to an estimate for the fraction of pyphenidon metabolized by CYP1A2 in vivo To 1.28 and 1.35 to 1.52.

Table 4: Predicted effects of co-administered 250 or 500 mg doses of ciprofloxacin on pypenidone PK under various hypothetical scenarios for the pypnnidone fraction metabolized by CYP1A2

CYP1A2  Other CYP's  Virtual Suppression

Simulations were also conducted to predict the likelihood of drug-drug interactions with co-inhibitors of CYPs other than CYP1A2, such as CYP2C9, 2C19, 2D6 and 2E1. Considering the fact that these other CYPs contribute to a smaller fraction of the in vivo metabolism of pypenidone, we simulated a hypothetical scenario in which the drug has the theoretical capacity to completely inhibit one or more of CYP2C9, 2C19, 2D6 and 2E1 . As shown in Table 5 below, complete inhibition of all four of these CYPs would only be predicted to result in an 8% increase in pypnidone AUC. Suppressing only one of these complementary pathways would not be expected to cause any increase in pyruvate donor AUC. It should be noted that this simulation assumes that CYP1A2 is fully functional.

Table 5 Predicted effects of hypothetical inhibitors of CYP2C9, 2C19, 2D6 and / or 2E1 on PK exposure to concurrently administered pyrpennidone

IVIVE  Relevance of simulation results

Ciprofloxacin blocks the single, but major, pathway (CYP1A2) of the pypnidone metabolite. By comprehensively considering all relevant in vitro and in vivo data on pyrepenidone in conjunction with IVIVE simulations, it is suggested that CYP1A2 is responsible for 70-80% of the pyrethroids in vivo metabolism (see Table 6 below) Lt; / RTI > From the IVIVE simulations, in which much lower or higher fractions were metabolized by CYP1A2, the ΔAUC predictions were obtained that did not match the AUC ratios observed in the Phase 1 clinical trial (see Example 1).

[Table 6] Comparison of IVIVE simulation results with observed values from step 1 drug-drug interaction studies (described in Example 1)

While this disclosure has been described in terms of various embodiments and examples, it is understood that variations and improvements will occur to those skilled in the art.

Claims (15)

The method of claim 1, wherein the dose of pyripenidone administered to the patient is reduced by about 1/2 to about 1/3 during the simultaneous administration of ciprofloxacin at a dose of 750 mg (1500 mg / day) twice daily. An improved method of administration of therapy. Administering a therapeutically effective amount of pypenidone to a patient in need of treatment with pypenidone and avoiding simultaneous administration of ciprofloxacin in a dose of 750 mg. 4. The method of claim 1, wherein during the administration of ciprofloxacin, the pyrennidone dose is reduced to a dose in the range of from about 2403 mg / day to about 1400 mg / day to about 1650 mg / day, optionally to 1602 mg / day. 3. The method of claim 1, wherein during the administration of ciprofloxacin, said pypnidol dose is reduced from about 1800 mg / day to a dosage ranging from about 1000 mg / day to about 1250 mg / day, optionally to 1200 mg / day. The method according to any one of claims 1 to 4, wherein the method is intended to avoid the possibility of reducing the clearance rate of pypnnidone or increasing the exposure to pypnnidone. 6. The method according to any one of claims 1 to 5, wherein said total daily dose of pyperidone is administered to said patient in a divided dose three times per day, with the food. 7. The method according to any one of claims 1 to 6, wherein the pyrennidone is administered in a unit dosage form which is a capsule or tablet. 8. The method of claim 7, wherein said amount of pyperidon in said unit dosage form is 200 mg or 267 mg. 4. The method according to claim 3, wherein, during simultaneous administration of ciprofloxacin, 534 mg of pyruvate is administered to the patient three times a day with food. 4. The method of claim 3, wherein during simultaneous administration of ciprofloxacin, the pypnnidone is administered in a total daily dose of 1602 mg. 4. The method of claim 3 wherein during simultaneous administration of ciprofloxacin, the pypnidol is administered in a total daily dose of about 1600 mg. 12. The method of any one of claims 1 to 11, wherein said patient is suffering from idiopathic pulmonary fibrosis (IPF). 12. A method according to any one of claims 1 to 11, wherein the patient is suffering from a fibrosing disorder, an inflammatory disorder, or an autoimmune disorder. 12. The method according to any one of claims 1 to 11, wherein said patient is at least one of the following: (1) a patient with atypical pulmonary fibrosis, pulmonary fibrosis, bronchiolitis obliterans, chronic lung transplant rejection, scleroderma, primary focal segmental glomerulosclerosis (FSGC) MPGN), idiopathic interstitial pneumonia, interstitial lung disease in pulmonary fibrosis, autoimmune pulmonary disease, benign prostatic hypertrophy, coronary or myocardial infarction, atrial fibrillation, cerebral infarction, myocardial fibrosis, musculoskeletal fibrosis, , Chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), hepatocellular carcinoma, Inflammatory pulmonary fibrosis, rheumatoid arthritis; Rheumatic spondylitis; Osteoarthritis; Gout, other arthritic diseases; blood poisoning; Septic shock; Endotoxic shock; Gram-negative sepsis; Toxic shock syndrome; Myofascial pain syndrome (MPS); Sialolithiasis; asthma; Adult respiratory distress syndrome; Inflammatory bowel disease; Crohn's disease; psoriasis; eczema; Ulcerative colitis; Glomerulonephritis; Scleroderma; Chronic thyroiditis; Graves' disease; Ormond disease; Autoimmune gastritis; Myasthenia gravis; Autoimmune hemolytic anemia; Autoimmune neutropenia; Thrombocytopenia; Pancreatic fibrosis; Chronic active hepatitis including liver fibrosis; Acute or chronic renal disease; Renal fibrosis; Diabetic nephropathy; Irritable bowel syndrome; Pyresis; Stenosis; Brain malaria; Stroke or ischemic injury; Neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; Acute or chronic pain; Allergies including allergic rhinitis or allergic conjunctivitis; Cardiac hypertrophy, chronic heart failure; Acute coronary syndrome; cachexy; malaria; leprosy; Rishmaniasis; Lyme disease; Lighter syndrome; Acute synovitis; Muscular degeneration, bursitis; Tendonitis; Hay fever; Ruptured, destroyed, or escaped vertebral disc syndrome; Bone calcification; thrombosis; Silicosis; Pulmonary sarcoidosis; Bone resorption diseases such as osteoporosis or multiple myeloma-related bone disorders; Cancer including but not limited to metastatic breast carcinoma, colorectal carcinoma, malignant melanoma, gastric cancer, or non-small cell lung cancer; Graft versus host response; Or autoimmune diseases such as multiple sclerosis, lupus or fibromyalgia; AIDS or other viral diseases such as herpes zoster, herpes simplex I or II, influenza virus, severe acute respiratory syndrome (SARS) or cytomegalovirus; Or breast cancer, including diabetes, proliferative disorders (including benign or malignant hyperplasias), acute myelogenous leukemia, chronic myelogenous leukemia, Kaposi sarcoma, metastatic melanoma, multiple myeloma, metastatic breast carcinoma; Colon rectal carcinoma; Malignant melanoma; Gastric cancer; Non-small cell lung cancer (NSCLC); Bone metastasis; Pain disorders including neuromuscular pain, headache, cancer pain, toothache, or arthritis pain; An angiogenic disorder including solid tumor angiogenesis, intraocular angiogenesis, or infantile hemangioma; A disease associated with a cyclooxygenase or lipoxygenase signaling pathway, including diseases associated with prostaglandin endoperoxide synthase-2 (including edema, fever, analgesia, or pain); Tracheal hypoxia; Thrombin induced platelet aggregation; Or a prophylactic disease. (b) a package insert, package label, instruction sheet or other labeling for the method according to any one of claims 1 to 14, optionally in a container.

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